Raghunathan, Aditya

AbstractBackgroundMeningiomas are the most common primary central nervous system (CNS) tumor in adults and CNS World Health Organization grade 2 (atypical) meningiomas show an intermediate risk of recurrence/progression. Molecular parameters are needed to better inform management following gross total resection (GTR).MethodsWe performed comprehensive genomic analysis of tumor tissue from 63 patients who underwent radiologically confirmed GTR of a primary grade 2 meningioma, including a CLIA-certified target next-generation sequencing panel (n = 61), chromosomal microarray (n = 63), genome-wide methylation profiling (n = 62), H3K27me3 immunohistochemistry (n = 62), and RNA-sequencing (n = 19). Genomic features were correlated with long-term clinical outcomes (median follow-up: 10 years) using Cox proportional hazards regression modeling and published molecular prognostic signatures were evaluated.ResultsThe presence of specific copy number variants (CNVs), including -1p, -10q, -7p, and -4p, was the strongest predictor of decreased recurrence-free survival (RFS) within our cohort (P < .05). NF2 mutations were frequent (51%) but did not show a significant association with RFS. DNA methylation-based classification assigned tumors to DKFZ Heidelberg benign (52%) or intermediate (47%) meningioma subclasses and was not associated with RFS. H3K27 trimethylation (H3K27me3) was unequivocally lost in 4 tumors, insufficient for RFS analysis. Application of published integrated histologic/molecular grading systems did not improve prediction of recurrence risk over the presence of -1p or -10q alone.ConclusionsCNVs are strong predictors of RFS in grade 2 meningiomas following GTR. Our study supports incorporation of CNV profiling into clinical evaluation to better guide postoperative patient management, which can be readily implemented using existing, clinically validated technologies.

Abstract Primary leptomeningeal lymphoma is exceedingly rare. We describe 2 rare lymphoma cases with exclusive leptomeningeal disease: 1 ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) and 1 primary effusion lymphoma (PEL). Case 1: A 19-year-old man presented with symptoms concerning for leptomeningitis. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis. Spine MRI demonstrated pial enhancement from T10 through the conus medullaris and cauda equina enhancement/thickening. A biopsy showed leptomeningeal involvement by large lymphoma cells with hallmark cells and brisk mitotic activity. By immunohistochemistry, cells were CD7/CD30-positive with cytoplasmic ALK staining. No systemic disease was identified. The diagnosis of primary leptomeningeal ALK+ ALCL was made. Despite 2 CSF relapses requiring systemic therapy and autologous bone marrow transplant, the patient was in complete clinical remission 9 years after the diagnosis. Case 2: A 60-year-old, human immunodeficiency virus-positive man presented with symptoms suggestive of leptomeningitis. Brain MRIs revealed multifocal, supratentorial, and infratentorial leptomeningeal enhancement. A right frontal biopsy demonstrated leptomeningeal involvement by large lymphoma cells negative for B-cell immunostains, but CD138, MUM-1, and HHV8-positive, with aberrant CD3 expression. EBV-encoded RNA in situ hybridization was positive. In absence of solid lesions/extracranial involvement, the diagnosis of leptomeningeal PEL was rendered. Despite initial complete remission after chemotherapy, the patient died 9 months later.

Abstract Background Glioblastoma (GBM) has poor prognosis despite aggressive treatment. Dendritic cell (DC) vaccines are promising, but widespread clinical use has not been achieved, possibly reflecting manufacturing issues of antigen choice and DC potency. We previously optimized vaccine manufacture utilizing allogeneic human GBM tumor cell lysate and potent, mature autologous DCs. Here, we report a phase I study using this optimized DC vaccine in combination with standard therapy. Methods Following surgical resection and radiation with concurrent temozolomide (TMZ), newly diagnosed adult GBM patients received intradermal DC vaccines plus TMZ. Primary endpoints were safety and feasibility. Immune and treatment responses were recorded. Results Twenty-one patients were enrolled in this study. One progressed between leukapheresis and vaccine manufacture. Twenty patients received treatment per protocol. Vaccine doses (≥15) were generated following a single leukapheresis for each patient. No dose-limiting vaccine toxicities were encountered. One patient had symptomatic, histologically proven pseudoprogression. Median progression-free survival was 9.7 months. Median overall survival was 19 months. Overall survival was 25% at 2 years and 10% at 4 years. One patient remains progression-free 5 years after enrollment. Specific CD8 T-cell responses for the tumor-associated antigen gp100 were seen post-vaccination. Patients entered the trial with a leukocyte deficit compared to healthy donors which partly normalized over the course of therapy. Conclusions This vaccine platform is safe and highly feasible in combination with standard therapy for newly diagnosed patients. Imaging, histological, survival, and immunological data suggest a positive biological response to therapy that warrants further investigation.

Abstract ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

AbstractBackgroundOligodendroglioma is genetically defined by concomitant IDH (IDH1/IDH2) mutation and whole-arm 1p/19q codeletion. Codeletion of 1p/19q traditionally evaluated by fluorescence in situ hybridization (FISH) cannot distinguish partial from whole-arm 1p/19q codeletion. Partial 1p/19q codeletion called positive by FISH is diagnostically a “false-positive” result. Chromosomal microarray (CMA) discriminates partial from whole-arm 1p/19q codeletion. Herein, we aimed to estimate the frequency of partial 1p/19q codeletion that would lead to a false-positive FISH result.MethodsFISH 1p/19q codeletion test probe coordinates were mapped onto Oncoscan CMA data to determine the rate of partial 1p/19q codeletion predicted to be positive by FISH. Diffuse astrocytic gliomas with available CMA data (2015–2018) were evaluated and classified based on IDH1-R132H/ATRX/p53 immunohistochemistry, IDH/TERT promoter targeted sequencing, and/or CMA according to classification updates. Predicted false-positive cases were verified by FISH whenever possible.ResultsThe overall estimated false-positive FISH 1p/19q codeletion rate was 3.6% (8/223). Predicted false positives were verified by FISH in 6 (of 8) cases. False-positive rates did not differ significantly (P = .49) between IDH-mutant (4.6%; 4/86) and IDH-wildtype (2.9%; 4/137) tumors. IDH-wildtype false positives were all WHO grade IV, whereas IDH-mutant false positives spanned WHO grades II-IV. Testing for 1p/19q codeletion would not have been indicated for most false positives based on current classification recommendations.ConclusionSelective 1p/19q codeletion testing and cautious interpretation for conflicting FISH and histopathological findings are recommended to avoid potential misdiagnosis.

Subependymomas of the spinal cord are rare, do not often involve multiple levels, and very rarely recur. Here, we present a series of spinal cord subependymomas with a detailed description of the clinical, radiological and pathological features, and characterization by chromosomal microarray analysis. Briefly, the four patients included two men and two women, between the ages of 22 and 48 years. The most common presenting symptoms were neck and arm pain with upper extremity weakness. By imaging, the tumors were found to involve multiple spinal levels, including cervical/ cervico‐thoracic (three patients) and thoracic (one patient), were all eccentric, and had minimal to no post‐contrast enhancement. Two patients underwent gross total resection, one had a sub‐total resection, and one underwent biopsy alone with a decompressive laminectomy. Follow up ranged from 6 months to 22 years. One patient (case 4) had recurrence 15 years following gross total resection and chromosomal microarray analysis revealed deletions on the long arm of chromosome 6. Our limited series suggests that spinal cord subependymomas can rarely recur, even following gross total resection, suggesting a possible role for long‐term surveillance for these rare tumors.

We describe a gentleman diagnosed with a posterior fossa medulloblastoma in 1998, successfully treated with craniospinal radiation therapy (RT) and posterior fossa RT boost, followed by 12 months of adjuvant chemotherapy. Nineteen years later, at the age of 28, the patient presented with multiple cranial neuropathies and was found to have disseminated high-grade glioma with leptomeningeal dissemination. In addition to the salient features of this case, we provide a brief review of RT-induced malignancies and the need for further research regarding surveillance and prevention strategies.

AbstractAtypical teratoid/rhabdoid tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal tumors that contain a rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.